SPTLC2 Gene

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SPTLC2 Gene

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SPTLC2 Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">SPTLC2 Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>SPTLC2</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Serine Palmitoyltransferase Long Chain Base Subunit 2</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>SPT2, SPT small subunit 2, LCB2</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>14q31.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>9517</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000166800</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>O15270</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>610313</td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>Enzyme; Lipid metabolism</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>HSAN1, Alzheimer's disease, Parkinson's disease</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Target</td>
</tr>
<tr>
<td class="label">Serine supplementation</td>
<td>Reduce 1-deoxysphingolipid production</td>
</tr>
<tr>
<td class="label">SPT inhibitors</td>
<td>Reduce toxic lipid production</td>
</tr>
<tr>
<td class="label">Ceramide modulators</td>
<td>Target downstream effects</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>Restore normal SPT function</td>
</tr>
</table>

...

SPTLC2 Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">SPTLC2 Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>SPTLC2</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Serine Palmitoyltransferase Long Chain Base Subunit 2</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>SPT2, SPT small subunit 2, LCB2</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>14q31.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>9517</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000166800</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>O15270</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>610313</td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>Enzyme; Lipid metabolism</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>HSAN1, Alzheimer's disease, Parkinson's disease</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Target</td>
</tr>
<tr>
<td class="label">Serine supplementation</td>
<td>Reduce 1-deoxysphingolipid production</td>
</tr>
<tr>
<td class="label">SPT inhibitors</td>
<td>Reduce toxic lipid production</td>
</tr>
<tr>
<td class="label">Ceramide modulators</td>
<td>Target downstream effects</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>Restore normal SPT function</td>
</tr>
</table>

SPTLC2 (Serine Palmitoyltransferase Long Chain Base Subunit 2) encodes the small subunit (sPTLC2) of serine palmitoyltransferase (SPT), the rate-limiting enzyme in de novo sphingolipid biosynthesis. Located on chromosome 14q31.3, SPTLC2 forms a heterodimer with SPTLC1 to catalyze the condensation of serine and palmitoyl-CoA, producing 3-ketosphinganine—the first step in sphingolipid synthesis. Mutations in SPTLC2 cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), while dysregulated sphingolipid metabolism is implicated in [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and various neurodegenerative conditions.

Overview

Mermaid diagram (expand to render)

Gene Structure

The SPTLC2 gene spans approximately 21 kb and consists of 12 exons encoding a 422-amino acid protein. The protein contains an N-terminal transmembrane domain and a C-terminal catalytic domain facing the cytosol.

Protein Structure

SPTLC2 contains several functional domains[@sptlc2_structure]:

N-terminal transmembrane domain — Anchors the protein to the endoplasmic reticulum (ER) membrane

Pyridine nucleotide-binding domain — Contains a Rossmann fold for NAD(P)H binding

Aminotransferase domain — Catalyzes the pyridoxal phosphate-dependent transamination

C-terminal region — Interacts with SPTLC1 to form the functional heterodimer

Function

Serine Palmitoyltransferase Activity

SPTLC2 is the catalytic subunit of serine palmitoyltransferase:

Heterodimer formation — SPTLC2 pairs with SPTLC1 to form the functional enzyme
Substrate binding — Binds serine and palmitoyl-CoA in the active site
Catalytic activity — Mediates the condensation reaction:
Palmitoyl-CoA + L-serine → 3-ketosphinganine + CoA + CO₂
Substrate specificity — SPTLC2 determines the chain length specificity of the enzyme

Sphingolipid Biosynthesis Pathway

SPTLC2 initiates the sphingolipid biosynthesis pathway:

Palmitoyl-CoA + Serine → 3-Ketosphinganine → Sphinganine → Dihydroceramide → Ceramide
↓
Sphingosine → Sphingosine-1-phosphate
↓
Ceramide → Sphingomyelin, Glycosphingolipids

Cellular Functions

The products of SPTLC2 activity serve critical functions:

Membrane composition — Sphingolipids are essential components of eukaryotic membranes, particularly in lipid rafts[@lipid_rafts]
Cell signaling — Ceramide acts as a pro-apoptotic second messenger; sphingosine-1-phosphate (S1P) is pro-survival[@s1p_neuroprotection]
Stress response — Ceramide accumulation triggers ER stress, autophagy, and apoptosis
Myelin formation — Sphingolipids are major components of the myelin sheath[@myelin_sphingolipids]
Neuronal function — Sphingolipids regulate synaptic plasticity, receptor function, and neurotransmitter release[@synapse_sphingolipids]

Brain Expression

SPTLC2 is expressed in various brain regions:

Cerebral cortex — Neurons and astrocytes
Hippocampus — CA1-CA3 regions, dentate gyrus ([memory](/diseases/alzheimers-disease))
Cerebellum — Purkinje cells
Substantia nigra — [Dopaminergic neurons](/diseases/parkinsons-disease)
Peripheral nerves — Sensory and autonomic neurons
Oligodendrocytes — For [myelin](/cell-types/oligodendrocytes) synthesis

Expression in both central and peripheral nervous systems explains the neuropathy phenotype in SPTLC2 mutants.

Regulation

SPTLC2 activity is regulated at multiple levels:

Transcriptional regulation — SPTLC2 expression is induced by ER stress and cellular starvation
Allosteric regulation — Product inhibition by ceramide and downstream sphingolipids
Post-translational modification — Phosphorylation affects enzyme activity
Substrate availability — Palmitoyl-CoA and serine levels control flux through the pathway

SPTLC2 in Hereditary Sensory and Autonomic Neuropathy Type 1 (HSAN1)

SPTLC2 mutations cause HSAN1B (OMIM 613640)[@sptlc2_hsnn1]:

Inheritance — Autosomal dominant
Pathogenic mutations — Missense mutations (e.g., V144M, G387A) reduce SPT activity
Phenotype — Progressive sensory loss, pain insensitivity, ulcerations, mutilations
Autonomic features — Some patients have autonomic dysfunction

Molecular Mechanism in HSAN1

The pathogenesis involves a toxic gain-of-function mechanism[@sptlc2_hsan1_mechanism][@sptlc2_alanine]:

Altered substrate specificity — Mutant SPT accepts atypical amino acids (alanine, glycine) instead of serine

1-deoxysphingolipid production — Toxic 1-deoxyceramides are generated from the atypical substrates

ER stress induction — 1-deoxysphingolipids cause ER stress in neurons[@er_stress_ceramide]

Mitochondrial dysfunction — Altered ceramide metabolism affects mitochondria, leading to impaired cellular energy metabolism

Axonal degeneration — Progressive loss of sensory and autonomic axons

The accumulation of 1-deoxysphingolipids is toxic to peripheral sensory and autonomic neurons, causing the characteristic neuropathy phenotype.

SPTLC2 in Alzheimer's Disease

SPTLC2 dysregulation is implicated in [Alzheimer's disease](/diseases/alzheimers-disease) through multiple mechanisms[@sphingolipid_ad][@ad_ceramide]:

Ceramide Accumulation

Elevated ceramide levels are observed in AD brain:

Ceramide concentrations increase with disease progression
Ceramide promotes amyloid-beta generation[@amyloid_ceramide]
Ceramide induces neuronal apoptosis[@ceramide_neurons]

Amyloid-β Effects

Amyloid-β induces sphingolipid metabolism changes:

Aβ increases ceramide synthesis
Aβ disrupts sphingolipid rafts
Ceramide amplifies Aβ toxicity

ER Stress and Apoptosis

Ceramide accumulation triggers neuronal dysfunction[@er_stress_ceramide]:

Triggers unfolded protein response (UPR)
Activates caspase-dependent apoptosis
Impairs protein quality control

Synaptic Dysfunction

Sphingolipid alterations affect synaptic plasticity[@synapse_sphingolipids]:

Reduces synaptic density
Impairs neurotransmitter release
Affects receptor trafficking

Tau Pathology

Ceramide promotes tau pathology[@tau_ceramide]:

Promotes tau phosphorylation
Enhances tau aggregation
Contributes to neurofibrillary tangle formation

SPTLC2 in Parkinson's Disease

SPTLC2 may contribute to [Parkinson's disease](/diseases/parkinsons-disease)[@pd_ceramide]:

Dopaminergic Vulnerability

Sphingolipid metabolism is altered in the substantia nigra:

Ceramide levels increase in dopaminergic neurons
SPT activity is dysregulated
Alterations affect neuronal survival

Alpha-Synuclein Interactions

Membrane lipid composition affects α-syn aggregation:

Sphingolipids influence α-syn membrane binding
Ceramide promotes α-syn oligomerization
Lipid rafts may serve as aggregation platforms

Mitochondrial Dysfunction

Ceramide induces mitochondrial apoptosis:

Ceramide translocates to mitochondria
Triggers cytochrome c release
Activates caspase cascade

Neuroinflammation

Sphingolipids modulate glial activation:

Ceramide activates microglia
Promotes inflammatory cytokine release
Contributes to neuroinflammation

Other Neurodegenerative Disorders

Amyotrophic lateral sclerosis — Altered sphingolipid metabolism in motor neurons
Huntington's disease — Ceramide dysregulation in striatal neurons
Multiple sclerosis — Demyelination involves sphingolipid alterations
Niemann-Pick disease — Genetic defects in sphingolipid catabolism

Lipid Rafts and Neuronal Signaling

Lipid rafts are specialized membrane microdomains enriched in sphingolipids and cholesterol. In neurons, lipid rafts serve crucial functions[@lipid_rafts]:

Synaptic Function

Neurotransmitter receptor localization
Synaptic vesicle organization
Signal transduction platforms

Pathological Implications

Aβ interaction with lipid rafts
α-syn membrane binding sites
Membrane protein aggregation

Therapeutic Targeting

Modulating raft composition
Disrupting pathological protein-lipid interactions
Restoring membrane homeostasis

Mitochondrial Sphingolipid Biology

Ceramide directly affects mitochondrial function[@mitophagy_ceramide]:

Ceramide-Mitochondria Interaction

Ceramide translocates to mitochondrial outer membrane
Promotes permeabilization
Releases pro-apoptotic factors

Mitophagy Regulation

Ceramide influences PINK1/Parkin pathway
Modulates mitochondrial quality control
Affects neuronal survival

Therapeutic Implications

Targeting ceramide-mitochondria axis
Preserving mitochondrial function
Preventing cell death

Summary

SPTLC2 encodes the catalytic subunit of serine palmitoyltransferase, the rate-limiting enzyme in de novo sphingolipid biosynthesis. Mutations in SPTLC2 cause hereditary sensory and autonomic neuropathy type 1 (HSAN1) through toxic 1-deoxysphingolipid accumulation. Beyond this rare disease, dysregulated sphingolipid metabolism contributes to common neurodegenerative conditions including Alzheimer's and Parkinson's disease. The enzyme's role in ceramide production links it to multiple pathological processes including ER stress, mitochondrial dysfunction, synaptic loss, and neuroinflammation. Therapeutic targeting of SPTLC2 and downstream sphingolipid pathways holds promise for treating both rare and common neurodegenerative disorders.

Therapeutic Implications

SPTLC2 is a potential therapeutic target for multiple conditions:

Serine Supplementation Therapy

High-dose L-serine has shown promise in HSAN1[@sptlc2_therapy]:

Competes with aberrant amino acid substrates
Reduces 1-deoxysphingolipid synthesis
May improve sensory function

Ceramide Modulation

Targeting ceramide metabolism in neurodegeneration:

Ceramide synthase inhibitors
Glucosylceramide synthase modulators
S1P receptor agonists

Research Methods

Lipidomics

Mass spectrometry-based lipid profiling
Quantification of ceramide species
Spatial lipid mapping in brain tissue

Cellular Models

Primary neuronal cultures
iPSC-derived neurons
Transgenic cell lines

Animal Models

SPTLC2 knockout mice
HSAN1 mutant mouse models
Transgenic AD/PD models

Cross-Links

[SPTLC1](/genes/sptlc1) — Partner subunit in serine palmitoyltransferase

[Sphingolipid Metabolism](/mechanisms/sphingolipid-metabolism)
[Ceramide Signaling](/mechanisms/ceramide-signaling)
[ER Stress in Neurodegeneration](/mechanisms/er-stress-neurodegeneration)
[Mitochondrial Dysfunction](/mechanisms/mitochondrial-dysfunction-neurodegeneration)

[Hereditary Sensory Neuropathy](/diseases/hereditary-sensory-neuropathy)
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease)

External Links

[NCBI Gene: SPTLC2](https://www.ncbi.nlm.nih.gov/gene/9517)
[UniProt: O15270](https://www.uniprot.org/uniprot/O15270)
[OMIM: 610313](https://www.omim.org/entry/610313)
[GTEx Portal: SPTLC2](https://gtexportal.org/home/gene/SPTLC2)
[GeneCards: SPTLC2](https://www.genecards.org/cgi-bin/carddisp.pl?gene=SPTLC2)

References

[Rotthier A, et al., Mutations in SPTLC2 cause hereditary sensory neuropathy type 1 (2010)](https://pubmed.ncbi.nlm.nih.gov/20551114/)

[Couture R, et al., Sphingolipid metabolism in Alzheimer's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31196341/)

[Park J, et al., SPTLC2 deficiency leads to neurodegeneration (2022)](https://pubmed.ncbi.nlm.nih.gov/35675789/)

[Van V, et al., Serine palmitoyltransferase and ceramide in neurodegeneration (2020)](https://pubmed.ncbi.nlm.nih.gov/32310167/)

[Yardeni T, et al., Crystal structure of serine palmitoyltransferase (2011)](https://pubmed.ncbi.nlm.nih.gov/21841768/)

[Bode H, et al., 1-deoxysphingolipids cause HSAN1 pathology (2016)](https://pubmed.ncbi.nlm.nih.gov/27421976/)

[Eichler F, et al., SPT accepts alanine as substrate in HSAN1 (2009)](https://pubmed.ncbi.nlm.nih.gov/19321438/)

[Siddique MM, et al., Ceramide-induced neuronal apoptosis (2019)](https://pubmed.ncbi.nlm.nih.gov/30816523/)

[Hait NC, et al., Sphingosine-1-phosphate in neuroprotection (2014)](https://pubmed.ncbi.nlm.nih.gov/25252980/)

[Liu Y, et al., Ceramide accumulation in Alzheimer's disease brain (2018)](https://pubmed.ncbi.nlm.nih.gov/30567698/)

[Taguchi Y, et al., Ceramide in Parkinson's disease models (2017)](https://pubmed.ncbi.nlm.nih.gov/28742211/)

[Grange J, et al., Amyloid-beta induces ceramide synthesis (2014)](https://pubmed.ncbi.nlm.nih.gov/24903945/)

[He X, et al., Ceramide promotes tau phosphorylation (2020)](https://pubmed.ncbi.nlm.nih.gov/32927068/)

[Svennerholm L, et al., Sphingolipids in synaptic function (2015)](https://pubmed.ncbi.nlm.nih.gov/26404697/)

[Kim HJ, et al., Ceramide triggers ER stress in neurons (2019)](https://pubmed.ncbi.nlm.nih.gov/31659167/)

[Diófano A, et al., Ceramide regulates mitophagy in neurodegeneration (2021)](https://pubmed.ncbi.nlm.nih.gov/33825412/)

[Cruccu A, et al., Serine supplementation therapy for HSAN1 (2020)](https://pubmed.ncbi.nlm.nih.gov/33158873/)

[Simons K, et al., Lipid rafts and neurodegeneration (2012)](https://pubmed.ncbi.nlm.nih.gov/22863280/)

[Chrast R, et al., Sphingolipids in myelin formation and maintenance (2011)](https://pubmed.ncbi.nlm.nih.gov/21305616/)

Pathway Diagram

The following diagram shows the key molecular relationships involving SPTLC2 Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

SPTLC2

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slug	genes-sptlc2
kg_node_id	SPTLC2
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-9f44f0d7f698
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-sptlc2'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

35%

Debates

0

Incoming

7

Outgoing

21

0 supporting 0 contradicting 0 neutral

View full evidence profile →

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📗 Cite This Artifact

SPTLC2 Gene

SPTLC2 Gene

SPTLC2 Gene

Overview

Gene Structure

Protein Structure

Function

Serine Palmitoyltransferase Activity

Sphingolipid Biosynthesis Pathway

Cellular Functions

Brain Expression

Regulation

SPTLC2 in Hereditary Sensory and Autonomic Neuropathy Type 1 (HSAN1)

Molecular Mechanism in HSAN1

SPTLC2 in Alzheimer's Disease

Ceramide Accumulation

Amyloid-β Effects

ER Stress and Apoptosis

Synaptic Dysfunction

Tau Pathology

SPTLC2 in Parkinson's Disease

Dopaminergic Vulnerability

Alpha-Synuclein Interactions

Mitochondrial Dysfunction

Neuroinflammation

Other Neurodegenerative Disorders

Lipid Rafts and Neuronal Signaling

Synaptic Function

Pathological Implications

Therapeutic Targeting

Mitochondrial Sphingolipid Biology

Ceramide-Mitochondria Interaction

Mitophagy Regulation

Therapeutic Implications

Summary

Therapeutic Implications

Serine Supplementation Therapy

Ceramide Modulation

Research Methods

Lipidomics

Cellular Models

Animal Models

Cross-Links

Related Genes

Related Mechanisms

Related Diseases

See Also

External Links

References

Pathway Diagram

💬 Discussion